Brugada Syndrome via the RANGRF Gene

Brugada syndrome (BrS) is a potentially life-threating arrhythmia disorder without structural abnormalities, characterized by dizziness, syncope, nocturnal agonal respiration and sudden death. The classic electrocardiographic findings associated with BrS include ST segment elevation in leads V1 to V3, right bundle branch block, first degree AV block, and intraventricular conduction delay. BrS is much more common in men than in women, and many people who have BrS remain asymptomatic. Symptoms usually manifest during adulthood, but they may appear any time between two days and 80 years of age (Antzelevitch et al. 2005). BrS is treatable with preventive measures such as reducing fever, avoiding certain medications and using implantable cardiac defibrillator when necessary (Francis et al. 2005).

BrS is an autosomal dominant genetic disorder with variable expression, resulting from pathogenic variants within genes that encode cardiac ion channels. BrS is also referred to as a “cardiac channelopathy.” Pathogenic variants in 16 genes (CACNA1C, CACNB2, CACNA2D1, GPD1L, KCND3, KCNE3, KCNE5, KCNJ8, HCN4, RANGRF, SCN5A, SCN1B, SCN2B, SCN3B, SLMAP, and TRPM4) influencing sodium and calcium currents in the heart are associated with BrS and account for at least 26%-41% of cases of BrS (Kapplinger et al. 2010; Crotti et al. 2012). Most patients with BrS have inherited a disease-causing variant from a parent, as de novo pathogenic variants in BrS are rare (Hedley et al. 2009).

The RANGRF gene (RAN Guanine Nucleotide Release Factor) contains five exons and is located at chromosome 17p13.1. Human MOG1, encoded by RANGRF, binds to Ran-GTP complex and Ran (Ras-related GTPase) and is essential for the transport of protein and RNA in and out of the nucleus (Steggerda et al. 2000). The cardiac sodium channel Nav1.5 is critical for heart function. Human MOG1 also interacts with the cytoplasmic loop II of Nav1.5 and modulates the expression and function of sodium channel Nav1.5 (Wu et al. 2008). A RANGRF loss-of- function pathogenic variant is linked to the physiopathology of Brugada Syndrome (Kattygnarath et al. 2011). To date, the majority of reported pathogenic variants in the RANGRF gene have been missense or nonsense (Human Gene Mutation Database).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in RANGRF appear to be a rare cause of disease. Analytical sensitivity should be high because all reported pathogenic variants thus far are detectable by sequencing.

This test provides full coverage of all coding exons of the RANGRF gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).